Allylation of carbon pronucleophiles with alkynes in the presence of palladium/acetic acid catalyst

Article abstract of DOI:10.1002/adsc.200404046

We have developed an efficient and ecochemical process for the allylation of carbon pronucleophiles with alkynes. The reaction of alkynes with various active methynes and methylenes in the presence of Pd(PPh₃) ₄/acetic acid gave the corresponding allylated products in high yields and high regioselectivities. In the present catalytic system, the key is the use of carboxylic acid which dramatically enhances the rate of the reactions. One of the important features of this process is that neither a leaving group is liberated nor is a stoichiometric amount of base needed to generate the nucleophiles.

Full text of DOI:10.1002/adsc.200404046

FULL PAPERS
Allylation of Carbon Pronucleophiles with Alkynes in the
Presence of Palladium/Acetic Acid Catalyst
Nitin T. Patil,a Isao Kadota,b Akinori Shibuya,a Young Soo Gyoung,a
Yoshinori Yamamotoa,*
a
Department ofChemistry, Graduate School ofScience, Tohoku University, Sendai 980-8578, Japan
Fax: (þ81)-22-217-6784, e-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
b
Research Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
Received: February 16, 2004; Accepted: May 7, 2004
th
Dedicated to Joe P. Richmond on the occasion ofhis 60 birthday.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/.
Abstract: We have developed an efficient and eco- ces the rate ofthe reactions. One ofthe important fea-
chemical process for the allylation of carbon pronu- tures ofthis process is that neither a leaving group is
cleophiles with alkynes. The reaction ofalkynes with
liberated nor is a stoichiometric amount ofbase need-
various active methynes and methylenes in the pres- ed to generate the nucleophiles.
ence ofPd(PPh )4/acetic acid gave the corresponding
3
allylated products in high yields and high regioselec- Keywords: alkynes; allylation; carbon nucleophiles,
À
tivities. In the present catalytic system, the key is C C bond formation; homogeneous catalysis; palladi-
the use ofcarboxylic acid which dramatically enhan-
um
Introduction
can overcome these problems is still needed. In this con-
text our group reported, in 1998, an entirely new method
for the allylation of carbon pronucleophiles with al-
kynes, which may serve as an alternative to the existing
The palladium-catalyzed allylation ofcarbon nucleo-
philes is wellrecognized as one ofthe most powerful syn-
thetic tools for the construction of carbon-carbon bonds, methods.[5a] In that communication, we reported the al-
Eq. (1).[1] In general, the method involves the use ofal-
lylation ofactive methynes with alkynes using the
lylic acetates, carbonates, halides, phosphates, NR2 etc.[2] Pd(PPh3)4/carboxylic acid combined catalytic system,
Eq. (2). It was our earlier observation that the allylation
proceeded smoothly with active methynes having two
cyano group, two SO2Ph groups, or one CN and one
COOEt group, giving the quaternary allylated products
in very high yields, Eq. (2).
ð1Þ
Recently, the direct use ofallylic alcohols is also gaining
much interest. Some efforts have been made in this di-
rection by the use ofactivators, which coordinate with
ð2Þ
the hydroxy group ofallylic alcohols thereby increasing
their leaving group ability.[3] However, these transfor-
mations are not necessarily the best procedure for the al-
lylation ofcarbon nucleophiles rfom an eco-chemical Encouraged by these results and motivated by the im-
point ofview, since the use ofa stoichiometric amount
portance ofa regioselective carbon-carbon bond form-
ofbase is needed to generate nucleophiles (Nu À) from ing process, we attempted the allylation ofactive meth-
pronucleophiles (H-Nu) and a stoichiometric amount ylenes as they would have more synthetic potential. Ac-
[4]
ofa leaving group (X) is liberated. Research in this cordingly, we attempted the allylation ofmalononitrile [6]
field seeking a new and more efficient method which under the established procedure; however, the product
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DOI: 10.1002/adsc.200404046
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Allylation ofCarbon Pronucleophiles with Alkynes
FULL PAPERS
obtained was a mixture ofmono- and diallylated prod-
ucts. At this juncture, all attempts to control the mono-
allylation over diallylation failed. Accidental addition
ofdiethyl malonate to the reaction mixture led to a
breakthrough; the desired monoallylation took place
in high yield. Herein, we report a full account on the al-
lylation ofactive methylenes with alkynes together with
the previous findings, Eqs. (2) and (3).
ð3Þ
Scheme 1. Various active methynes and methylenes.
ed products in very high yields. The results are summar-
ized in Table 1.
We anticipated that this new palladium-catalyzed
transformation could be applied widely to the synthesis
ofnatural products ifwe could extend this methodology
to the allylation ofactive methylenes. We selected malo-
Results and Discussion
Initially, we carried out the reaction of1-phenyl-1-pro-
pyne (13) with 1 equivalent ofmethylmalononitrile ( 1) nonitrile as a model substrate,[6] since the allylation of
in the presence of5 mol % Pd(PPh )4 as a catalyst in active methynes proceeded very well with methylmalo-
3
1,4-dioxane at 1008C. The reaction hardly proceeded, nonitrile and related substrates (1 5). The reaction of
and the desired product 14 was obtained in only a trace malononitrile (7; 1.2 equivs.) with 1-phenyl-1-propyne
amount. To our surprise, however, use ofacetic acid
(13; 1 equiv.) under the standard conditions, Pd(PPh3)4
(50 mol %) as an additive greatly improved the yield; (5 mol %)/CH3COOH (10 mol %)[8] in 1,4-dioxane at
14 was obtained in 99% (Table 1, entry 1). This rate en- 1008C, was carried out, Eq. (4): the diallylated product
hancement can be attributed to the cooperative effect of 42 was produced in 35% yield together with the monoal-
both the palladium catalyst and acetic acid, because ei- lylated product 41 in 35% yield (Table 2, entry 1). This
ther ofthe individual reagents alone did not give the
observation suggested that the allylation proceeded
with malononitrile and the monoallylated malononitrile
product.[7] A variety ofproton sources was then exam-
ined; among the tested acetic acid, trifluoroacetic acid, was more reactive than the original substrate, malononi-
benzenesulfonic acid, and HCl, acetic acid gave the trile. At this stage, we believed that the selective and
best result. Next, we examined different palladium cat- synthetically useful allylation reaction with alkynes
alysts and phosphine ligands. Among the palladium cat- was restricted to active methynes bearing a CN or
alyst examined, Pd(PPh3)4 and thePd2(dba)3 ¥CHCl3/ SO2Ph group only. However, the accidental addition of
PPh3 combination gave the best results, however, in diethyl malonate to the reaction mixture changed the
the latter case the reaction was slightly slower. The com- mode ofreaction giving the monoallylated product se-
bination ofPd(OAc) (5 mol %) with PPh3 (10 mol %) lectively. Our dream, although after a long gap, was ful-
2
could also be used, however, the reaction was slower filled. Various active methylenes turned out to be appli-
and it took a longer time to reach completion (30 h). cable for the selective monoallylation. Perhaps the low-
The use ofbidentate ligands, such as dppb and dpp,f
er acidity ofmethylene protons ofdiethyl malonate
with Pd(PPh3)4 or Pd2(dba)3 ¥CHCl3 inhibited the reac- hampers the formation of the diallylated product. The
tion completely. Besides these investigations, this hydro- results are summarized in Table 2.
carbonation reaction was examined in the presence of
water (20 mol %) as an additive. Thus, the reaction of
13 with 1 in the presence ofPd(PPh )4 (5 mol %)/
3
CH3COOH (10 mol %)/water (20 mol %) afforded 14
in 99% yield, indicating that the reaction was not sensi-
tive to moisture.
ð4Þ
After studying various palladium sources, phosphine
ligands and additives, we then employed the Pd(PPh3)4
(5 mol %)/CH3COOH (50 mol %) catalytic system for
the hydrocarbonation ofalkynes with several active me-
At first, the treatment of 1-phenyl-1-propyne (13) with
thynes. The allylation proceeded smoothly with active one equivalent ofdiethyl malonate ( 8) under the stand-
methynes 1 5 (Scheme 1) giving the quaternary allylat- ard conditions gave the monoallylated product 43 in
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Nitin T. Patil et al.
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Table 1. Pd(0)/AcOH-catalyzed allylation ofactive methynes
Table 2. Pd(PPh3)4/AcOH-catalyzed allylation ofactive me-
with alkynes.[a]
thylenes with various alkynes.[a]
[a]
50 mol% acetic acid was used in all the cases.
Yield ofisolated product.
[b]
[c]
Inseparable mixture ofregioisomers. Ratios were deter-
1
mined by H NMR analysis.
[a]
All reactions were carried out with 5 mol % ofPd(PPh )4
and 10 mol % acetic acid in 1,4-dioxane at 1008C for 12 h.
1.2 equivs. ofpronucleophiles were used.
Yields ofisolated products based on alkynes.
3
71% yield with the formation of the diallylated product
in 10% yield. The formation of the diallylated product
was totally suppressed by the use of1.2 equivalents ofdi-
ethyl malonate giving 43 in 92% isolated yield (entry 1).
Similarly, the reaction of 13 with 1.2 equivs. of 9, 10 and
[b]
[c]
11 gave the monoallylated products 44, 45 and 46, re- er 54 in 68% yield while another regioisomer could not
spectively, in good to high yields (entries 2 4), and the be detected at all (entry 9).
corresponding diallylated products were not isolated.
However, in the case of 12, a mixture ofmono- and di-
allylated products 47 and 48 was obtained (entry 5).
A proposed mechanism for the allylation of C-nucle-
ophiles with alkynes under Pd(0)/acetic acid is shown
in Scheme 2. The initial step would be hydropalladation
Tetrolic acid ethyl ester (49) also reacted smoothly of 13 with the hydridopalladium species 55 generated
with the nucleophiles 8, 9 and 10 to give the monoallylat- from Pd0 and acetic acid (catalytic cycle I).[7a] The result-
ed products 50, 51, and 52, respectively, in high yields ing vinylpalladium species 56 would produce phenylal-
(entries 6 8). The reaction ofthe N-Boc protected lene 57 and the active catalyst 55 via b-elimination.[9]
propargylamine derivative 53 gave only one regioisom- Hydropalladation of 57 with 55 would give the p-allyl-
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Allylation ofCarbon Pronucleophiles with Alkynes
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concentrated. The residue was purified by a silica gel column
chromatography (hexane/AcOEt, 4:1) to give 43; yield:
0.44 g (92%).
Supporting Information
Experimental details, characterization data ofall compounds,
1H NMR spectral data ofcompounds 43 48 and 50 54 (15 pa-
ges).
Acknowledgements
NTP thanks the Japan Society for the Promotion of Science
(JSPS)for a postdoctoral research fellowship.
Scheme 2. Proposed mechanism for the allylation of C-nucle-
ophiles with alkynes.
References and Notes
palladium species 58 which reacts with a pronucleophile
to give the product 14 along with the hydridopalladium
55 (cycle II).
[1] For recent reviews, see: a) S. Godleski, in: Comprehensive
Organic Synthesis, (Eds.: B. M. Trost, I. Fleming), Vol.
4,Pergamon Press, New York, 1991, pp. 585 661; b) J. A.
Davies, in: Comprehensive Organometallic Chemistry II,
(Eds.: G. Wilkinson, F. G. A. Stone, E. W. Abel), Vol. 9,
Pergamon Press, Oxford, 1995, pp. 291 390; c) J. Tsuji,
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Consiglio, R. M. Waymouth, Chem. Rev. 1989, 89, 257
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wamura, R. Kiyotake, K. Kudo, Chirality, 2002, 14, 724
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Conclusions
In summary, we have developed an efficient method for
the allylation ofcarbon pronucleophiles with simple al-
kynes using the palladium/acetic acid combined catalyt-
ic system. Thus, we are now in a position to allylate a va-
riety ofactive methylenes and methynes by using this
newly developed procedure. The reaction possesses sev-
eral synthetically attractive features: (1) simple proce-
dure allowing large-scale preparation, (2) high regiose-
lectivity, (3) the ease ofthe preparation ofthe substrates,
especially in the case ofthe intramolecular reactions, [5a]
(4) no base is needed to generate the nucleophile, (5) no
need for dry solvent, (6) possibility of asymmetric ver-
sion. Furthermore, to the best ofour knowledge, the
present reaction is the first example for the formal allylic
substitution reaction with simple alkynes, which enables
one to carry out an eco-chemical process without liber-
ating leaving groups. Further attempts to make this reac-
tion enantioselective, are now underway in our labora-
tory.
[2] J. Tsuji, Transition Metal Reagents and Catalysts, Wiley,
New York, 2000, Chapter 4.
[3] The following inorganic acid anhydrides have been used
as an activator: a) As2O3: X. Lu, L. Lu, S. Junhui, J.
Mol. Cat. 1987, 41, 245; b) B2O3: X. Lu, X. Jiang, X.
Tao, J. Organomet. Chem. 1988, 344, 109; c) CO2: M. Saka-
moto, I. Shimizu, A. Yamamoto, Bull. Chem. Soc. Jpn.
1996, 69, 1065; d) F. Ozawa, H. Okamoto, S. Kawagishi,
S. Yamamoto, T. Minami, M. Yoshifuji, J. Am. Chem.
Soc. 2002, 124, 10968 10969 and references cited therein.
[4] Although allylic carbonates and epoxides react with pro-
nucleophiles in the absence ofan external base, a stoichio-
metric amount ofalkoxides generated from the substrates
acts as a base in these reactions.
Experimental Section
Reaction of Methylmalonontrile with 1-Phenyl-1-
Propyne; Typical Procedure
To a mixture of1-phenyl-1-propyne 13 (0.20 g, 1.72 mmol), di-
ethyl malonate 8 (0.33 g, 2.07 mmol), Pd(PPh3)4 (0.099 g,
0.086 mmol) in dry 1,4-dioxane (5 mL) was added acetic acid
(0.010 g, 0.17 mmol), and the mixture was stirred for 12 h at
1008C. The reaction mixture was then filtered through a short
silica gel column using ether as an eluent, and the filtrate was
[5] For preliminary communication, see: a) I. Kadota, A. Shi-
buya, Y. S. Gyoung, Y. Yamamoto, J. Am. Chem. Soc. 199
8, 120, 10262 10263; during the course ofthese studies,
we also reported the hydroamination and hydroalkoxyla-
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Nitin T. Patil et al.
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ton ofalkynes, see: b) I. Kadota, A. Shibuya, M. L. Lutete,
Y. Yamamoto, J. Org. Chem. 1999, 64, 4570 4571;
c) M. L. Lutete, I. Kadota, A. Shibuya, Y. Yamamoto,
Heterocycles. 2002, 58, 347 357; d) I. Kadota, M. L. Lu-
tete, A. Shibuya, Y. Yamamoto, Tetrahedron Lett. 2001,
42, 6207 6210. While the work was in progress, another
group reported the hydrocarboxylation ofalkynes based
on the same concept, see: e) W. Zhang, A. R Haight,
M. C. Hsu, Tetrahedron Lett. 2002, 43, 6575 6578. We
also reported, previously, the hydrocarbonaton ofthe sub-
strates other than alkynes. For hydrocarbonation ofal-
lenes, see: f) Y. Yamamoto, M. Al-Masum, N. Asao, J.
Am. Chem. Soc. 1994, 116, 6019 6020; g) Y. Yamamoto,
M. Al-Masum, N. Fujiwara, Chem. Commun. 1996, 381
382; h) Y. Yamamoto, M. Al-Masum, A. Takeda, Chem.
Commun. 1996, 831 832; i) Y. Yamamoto, M. Al-Masum,
N. Fujiwara, N. Asao, Tetrahedron Lett. 1995, 36, 2811
2814; j) Y. Yamamoto, M. Al-Masum, Synlett 1995, 969
970; k) M. Meguro, S. Kamijo, Y. Yamamoto, Tetrahedron
Lett. 1996, 37, 7453 7456. For the hydrocarbonation of
1,3-enynes, see: l) M. M. Salter, V. Gevorgyan, S. Saito,
Y. Yamamoto, Chem. Commun. 1996, 17; for the hydro-
carbonation of3,3-dihexylcyclopropene, see: m) I. Naka-
mura, G. B. Bajracharya, Y. Yamamoto, J. Org. Chem.
2003, 68, 2297 2299. For the hydrocarbonation ofmethyl-
eneaziridines, see: n) B. H. Oh, I. Nakamura, Y. Yamamo-
to, Tetrahedron Lett. 2002, 43, 9625 9628. For the hydro-
carbonation ofmethylenecyclopropanes, see: o) N. Tsuka-
da, A. Shibuya, I. Nakamura, Y. Yamamoto, J. Am. Chem.
Soc. 1997, 119, 8123; p) N. Tsukada, A. Shibuya, I. Naka-
mura, H. Kitahara, Y. Yamamoto, Tetrahedron 1999, 55,
8833.
[6] It was also reported in ref.[5a] that the allylation ofdiethyl
methylmalonate was very sluggish and only a trace
amount ofthe corresponding allylated product was ob-
tained even after prolonged reaction time. At this stage,
we believed that the allylation reaction was restricted to
active methynes, bearing less bulky and strong electron-
withdrawing groups such as CN and SO2Ph. Therefore,
we chose malononitrile as a model substrate for active
methylenes.
[7] Enhancement ofreaction rate by the use ofPd(0)/carbox-
ylic acid combined catalytic system is also observed by
others, see: a) B. M. Trost, F. Rise, J. Am. Chem. Soc. 19
87, 109, 3161 3163; b) B. M. Trost, C. Jakel, B. Plietker,
J. Am. Chem. Soc. 2003, 125, 4438 4439.
[8] Initially we used 50 mol % ofacetic acid in the reactions
as reported in the previous communication,[5a] but later
found that 10 mol % of acetic acid was also enough with-
out affecting the reaction in terms of yield, time and regio-
selectivity.
[9] Palladium-catalyzed isomerization ofalkynes to allenes,
see: a) H. Sheng, S. Lin, Y. Huang, Tetrahedron Lett. 19
86, 27, 4893 4894; b) B. M. Trost, T. Schmidt, J. Am.
Chem. Soc. 1988, 110, 2301 2303; c) X. Lu, J. Ji, D. Ma,
W. Shen, J. Org. Chem. 1991, 56, 5774 5778.
804
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